CARDIA Y35 Brain MRI Renewal Ancillary Study Abstract Many studies have established strong relationships between cerebrovascular disease (CEVD), morphological and physiological brain changes, including stroke, and cognitive decline and dementia, including Alzheimer disease and related disorders (ADRD). New physiological and functional MRI (fMRI) methods allow non- invasive measurement of regional cerebral blood flow, vascular reactivity and physiological brain connectivity. These techniques provide the means to evaluate the morphology, pathophysiology, and brain dysfunction related to CEVD and ADRD. The CARDIA Year 25 and Year 30 Brain MRI Substudies were designed to incorporate state-of-the-art MRI technology into the relatively younger population of CARDIA in order to determine MRI correlates of CVD risk factors and detect early CEVD. These studies documented early MRI changes of CEVD with strong correlations to CVD risk factors, particularly hypertension. The CARDIA Year 35 MRI Ancillary Study is intended to extend these earlier studies into the late middle age population of CARDIA. Most biomarkers of CEVD and ADRD are weakly expressed until approximately age 55, when they begin their precipitous rise to the steep slope evident in the 6th and 7th decades of life. Correspondingly, subclinical disease becomes clinically evident, reflected by increasing physiological changes and cognitive deficits. However, confounding the effects of CEVD are age, lifestyle, and co-morbidities, including ADRD. CARDIA, with its lengthy and rich historical data, is well-positioned to dissect the intricacies of CEVD and putative relationship to ADRD in the transition from middle age to seniority, starting at ages with few comorbidities and low medication use. Approximately 1044 participants will be enrolled in the Ancillary Study from the four participating Field Centers. MRI participants will be recruited from previous CARDIA Brain MRI participants and receive brain MRI scans and cognitive testing as defined for Y25 and Y30. Computer analysis of MRI data will be reported quantitatively by anatomic regions-of-interest. The primary objectives are to: 1) enhance statistical power to better document previously described and newly defined associations between demographic measures, risk factors and brain MRI findings, 2) define MRI parameters most strongly associated with clinical events and cognitive changes, and 3) identify early MRI biomarker patterns that inform disease pathophysiology and progression at an individual level.